Astrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells

Abstract

Astrocytes are important regulators of excitatory synaptic networks. However, astrocytes regulation of inhibitory synaptic systems remains ill defined. This is particularly relevant since GABAergic interneurons regulate the activity of excitatory cells and shape network function. To address this issue, we combined optogenetics and pharmacological approaches, two-photon confocal imaging and whole-cell recordings to specifically activate hippocampal somatostatin or paravalbumin-expressing interneurons (SOM-INs or PV-INs), while monitoring inhibitory synaptic currents in pyramidal cells and Ca2+ responses in astrocytes. We found that astrocytes detect SOM-IN synaptic activity via GABABR and GAT-3-dependent Ca2+ signaling mechanisms, the latter triggering the release of ATP. In turn, ATP is converted into adenosine, activating A1Rs and upregulating SOM-IN synaptic inhibition of pyramidal cells, but not PV-IN inhibition. Our findings uncover functional interactions between a specific subpopulation of interneurons, astrocytes and pyramidal cells, involved in positive feedback autoregulation of dendritic inhibition of pyramidal cells.

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…An independent study using an acute CORT administration protocol found a decrease in astrocytic gap‐junction channel expression (Quesseveur et al, ), indicating that there are measurable effects of CORT treatment on astrocytes. Considering the strong role of astrocytes in tuning synaptic transmission and plasticity through various mechanisms (Gordon et al, ; Henneberger, Papouin, Oliet, & Rusakov, ; Matos et al, ; Morquette et al, ; Murphy‐Royal, Dupuis, Groc, & Oliet, ; Panatier et al, ), it is possible that CORT along with neuromodulators released during the central stress response such as corticotropin releasing hormone or noradrenaline can act synergistically on astrocytes to induce the release of gliotransmitters, impacting synaptic plasticity. Evidence for the synergistic action of neuromodulators alongside classical neurotransmitters (such as glutamate) acting on astrocytes to modulate synaptic plasticity was recently demonstrated (Crosby et al, ).…”

GABAergic‐astrocyte signaling: A refinement of inhibitory brain networks

“…These data indicate that astrocytes can decode the frequency and duration of interneuron activity by releasing different gliotransmitters and evoking a biphasic synaptic modulation of CA3‐CA1 synapses (Covelo & Araque, ). However, other studies in hippocampus and somatosensory cortex found that shorter durations (5 or 10 s) or different frequencies (2 or 40 Hz) of GABAergic activity were sufficient to engage astrocytic Ca 2+ signaling (Deemyad et al, ; Mariotti et al, ; Matos et al, ; Perea et al, ) and synaptic‐derived modulation (Deemyad et al, ; Matos et al, ; Perea et al, ). Therefore, the broad spectrum of GABAergic actions on astrocytic physiology needs to be clarified, such as whether GABAergic‐astrocyte signaling express particular features in different brain areas, and its dependence on the interneuron firing rate, that is, duration and frequency.…”

“…Thus, it has been found that GABA released during sparse low interneuron activity, that is, single action potentials or low firing rate during short periods by direct depolarization or optogenetic stimulation, does not stimulate Ca 2+ signaling at the soma or unresolved domains in hippocampal and cortical astrocytes (Deemyad, Luthi, & Spruston, ; Perea et al, ; Rozsa et al, ), even though it is able to reach the astrocyte membranes inducing inward currents (Rozsa et al, ). However, interneuron‐firing rates above 5 Hz or at lower rate over long periods did stimulate intracellular somatic and local Ca 2+ events in hippocampal astrocytes mediated by GABABRs and GAT‐3 (Covelo & Araque, ; Deemyad et al, ; Matos et al, ; Perea et al, ). In this scenario, whether astrocytes are recruited by enhanced or low but sustained GABAergic signaling, they would impact on hippocampal synaptic activity with different consequences.…”

“…Additionally, hippocampal astrocytes recruited by GABAergic activity can also release ATP/Ado (Andersson et al, ; Matos et al, ; Serrano et al, ). Hence, the same hippocampal circuit can experience potentiation and depression of excitatory synapses by GABAergic activation of astrocytes (Chen et al, ; Perea et al, ; Serrano et al, ), though the mechanisms motivating this dual effect are unclear.…”

“…In this study, most of the astrocytes recorded from layer 2–3 of the somatosensory cortex could be recruited by a second episode of SST firing, suggesting that intense activity in the SST interneuron circuit drives a long‐lasting activity in the astrocyte network (Mariotti et al, ). In this spirit, it has been reported that hippocampal astrocytes upregulate SST but not PV inhibitory synaptic transmission onto CA1 pyramidal cells via ATP/Ado release, which relies on activation of GAT‐3 in astrocytic membranes (Matos et al, ). However, it is unresolved whether the recorded astrocytes belong to different populations with specific preference for PV and SST GABAergic signaling, or there is a unique astrocyte population in the hippocampus that responds differently to both interneurons based on intrinsic cellular properties.…”